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Ann Thorac Surg 2011;91:574-579. doi:10.1016/j.athoracsur.2010.09.011
© 2011 The Society of Thoracic Surgeons
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Right arrow Lung - transplantation

Original Articles: Pediatric Cardiac

Lung Retransplantation in Children: Appropriate When Selectively Applied

Brandi B. Scully, BAa, Farhan Zafar, MDb, Marc G. Schecter, MDc, Joseph W. Rossano, MDd, George B. Mallory, Jr, MDc, Jeffrey S. Heinle, MDb, David L.S. Morales, MDb,*

a Congenital Heart Surgery, Texas Children's Hospital, Houston, Texas
b Michael E. DeBakey Department of Surgery, Division of Congenital Heart Surgery, Baylor College of Medicine, Houston, Texas
c Department of Pediatrics, Section of Pulmonology, Baylor College of Medicine, Houston, Texas
d Department of Pediatrics, Section of Cardiology, Baylor College of Medicine, Houston, Texas

Accepted for publication September 7, 2010.

* Address correspondence to Dr Morales, Congenital Heart Surgery, Texas Children's Hospital, 6621 Fannin St, MC-WT 19345H, Houston, TX 77030 (Email: dlmorale{at}texaschildrens.org).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 References
 
Background: Lung retransplantation (re-LTx) in children has been associated with lower survival rates compared with primary lung transplantation. However, improving survival for primary LTx has led to more patients presenting for re-LTx. Therefore, an analysis of the UNOS (United Network of Organ Sharing) database to evaluate the effectiveness of pediatric lung retransplantation in the United States was completed.

Methods: The UNOS registry was queried for pediatric re-LTx patients from May 1988 to May 2008. There were 81 (10%) re-LTx out of a total 802 pediatric lung transplants.

Results: Median age and weight at re-LTx were 14 (range, 0 to 18) years and 32 (4 to 58) kg. Indications for re-LTx were obliterative bronchiolitis in 50 patients (62%), primary graft failure in 8 (10%), and other in 23 (28%). The Kaplan-Meier graft survival for re-LTx patients was worse than for primary transplant patients (p < 0.001, graft half-life 0.9 vs 4.0 years), especially if re-LTx was done less than 1 year after primary transplant (graft half-life 0.25 years). Graft survival in patients who underwent re-LTx greater than 1 year after primary transplant was not statistically different than for primary LTx patients (p = 0.21; graft half-life 2.8 vs 4.0 years), and if re-LTx greater than 1 year posttransplant occurred in patients who were not ventilator dependent, survival was further improved (p = 0.68; graft half-life 4.7 vs 4.0 years).

Conclusions: Pediatric lung retransplantation within the first year after primary transplant does not appear advisable. Pediatric re-LTx greater than 1 year after primary transplantation may be a reasonable strategy for end-stage graft failure. Patients greater than 1 year posttransplant and not ventilator dependent appear an even more compelling group in which to consider lung retransplantation.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 References
 
Lung retransplantation (re-LTx) in children has historically been associated with higher morbidity and lower survival rates when compared with primary transplants, and enthusiasm for these procedures has thus been tempered [1–3]. However, for patients who develop graft failure from conditions such as bronchiolitis obliterans syndrome and acute graft dysfunction, retransplantation is often the only viable treatment. With the need far exceeding the number of available organs and the survival benefit of retransplantation in question, pediatric re-LTx has remained controversial.

In addition, although living donor lung transplantation for a time was thought to be an alternative to deceased donor lung transplantation in the pediatric re-LTx patient population, the number of these procedures reported in the International Society for Heart and Lung Transplantation (ISHLT) database has significantly decreased in recent years, from 14 done in 1999 to a total of 3 from 2005 to 2007 [1, 4]. The benefit of primary lung transplantation on survival has continued to be questioned, as only half of all grafts survive beyond 5 years, and only a quarter past 10 years [5, 6]. With the 2005 change in the allocation of donor lungs in the United States from a waiting time-based system to one based in part on one-year transplant survival benefit, survival after lung retransplantation should be carefully investigated to determine if this strategy is a responsible use of a limited resource. [7].

Despite the controversy, the 5-year survival for pediatric transplantation has improved significantly over time [1]. Therefore, more long-term survivors of pediatric lung transplantation present while still children or adolescents for lung retransplantation. A growing number of experienced centers have begun to perform pediatric lung retransplantation, especially in light of improving retransplantation results (an increase in 5-year survival for re-LTx patients from 32% to 41% over the past two years) being reported by the ISHLT [1]. The purpose of this study was to analyze the United Network of Organ Sharing (UNOS) database to evaluate the effectiveness of pediatric re-LTx in the United States.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 References
 
Patient Population
The UNOS registry was queried for pediatric (≤ 18 years old) lung retransplantation patients from May 1988 to May 2008. Approval was obtained from the Baylor College of Medicine Institutional Review Board; individual consent for the study was not needed. Analysis was limited to variables that were at least 80% populated. Twenty-five variables met this criterion and had an average capture rate of 95%. In addition to the 18 variables found in Table 1, an additional 6 variables (previous transplant, graft survival time, time to re-LTx, diagnosis at primary transplant, indication for re-LTx, and transplant year) were reported independently in the results. Patient survival was not reported since the primary focus of the manuscript was graft survival.


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  		Table 1 Preoperative and Perioperative Characteristics
 
Patient cohorts were created to differentiate between patient outcomes based on graft survival and ventilation status. Patient cohorts included primary lung transplant recipients, re-LTx patients, patients retransplanted after primary graft survival of less than 1 year, patients retransplanted after primary graft survival of greater than 1 year, and patients retransplanted after primary graft survival of greater than 1 year who were not ventilated at time of transplant.

Statistical Analysis
Statistical analyses were performed as follows: means, medians, standard deviations, and ranges were used to describe continuous variables. Frequencies and percentages were used for categoric data. The Fisher exact test and the {chi}2 test were used to analyze binary variables, and the Student's t test was used to analyze the continuous variables. Cox multivariate analysis was performed. For the Cox multivariable analysis, all factors were assessed simultaneously that had reached a threshold significance (p value of 0.1) under univariate analysis. Statistical significance was a probability value of less than 0.05. All analyses were conducted with the SPSS 15.0 (SPSS, Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 References
 
Patient Demographics
Between May 1988 and May 2008, 81 (10%) pediatric re-LTx were performed out of a total 802 pediatric lung transplants and 80% (65/81) of these re-LTx patients had their primary transplants recorded in UNOS. Figure 1 shows the number of retransplants by year, with patient age indicated. Median age and weight at re-LTx were 14 (range, 0 to 18) years and 32 kg (range, 4 to 58), respectively. Cystic fibrosis was by far the most common diagnosis at initial transplant, at 52% (n = 34), followed by idiopathic pulmonary hypertension, at 16% (n = 10), interstitial lung disease at 5% (n = 5), and "other" at 27% (n = 18). The indication for retransplantation was obliterative bronchiolitis in 50 patients (62%), primary graft failure in 8 patients (10%), and other types of graft failure in 23 patients (28%).


Figure 1
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  		Fig 1. Bar graph showing number of pediatric lung retransplants by year. ({square} = ≤ 1 year; {blacksquare} = 2 to 12 years; Figure 1 = 3 to 18 years.)

 
Median time to re-LTx was 2.3 years (range, 4 days to 12 years; see Fig 2). Preoperative and perioperative characteristics for both primary and retransplant patients can be found in Table 1. Of note, ventilator support was significantly increased in the re-LTx group preoperatively, while the weight for age of re-LTx patients was significantly less than that of primary transplant recipients. The re-LTx recipients were more likely to have a single lung transplant than primary lung transplant patients (p = 0.003). Drug-treated infection, length of hospital stay, and rejection prior to discharge were not significantly different between primary LTx and re-LTx cohorts (p > 0.05), while airway dehiscence was significantly increased in the re-LTx group postoperatively (p < 0.001).


Figure 2
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  		Fig 2. Bar graph depicting time to lung retransplant.

 
Morbidity and Mortality
Graft survival comparisons of primary and different cohorts of retransplant patients can be found in Table 2. The overall Kaplan-Meier graft survival (Fig 3) for re-LTx patients was significantly worse than for primary transplant patients, with five-year survival of 28% for retransplant patients versus 44% for primary transplant recipients (half life of 0.9 vs 4.0, p < 0.001). Graft survival for patients who were retransplanted less than one year from their primary LTx was further diminished (half life of 0.25 vs 4.0).


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  		Table 2 Kaplan-Meier Graft Survival for Different Cohorts of Pediatric Lung Transplantation Patients
 

Figure 3
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  		Fig 3. Kaplan-Meier graft survival curves, comparing primary transplant recipients with different cohorts of lung retransplant patients.

 
However, graft survival for patients who underwent re-LTx more than one year after primary transplant was not significantly different than graft survival for primary transplant recipients (half life of 2.8 vs 4.0, p = 0.21). Graft survival for patients who were retransplanted more than 1 year after initial transplant and who were not ventilator dependent was also not different from primary lung transplant graft survival (half life of 4.7 vs 4.0, p = 0.68).

Cox multivariate analysis identified chronic steroid use and ventilator support to be risk factors for mortality after re-LTx (see Table 3).


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  		Table 3 Multivariate Analysis of Risk Factors for Mortality After Retransplant
 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
References
 
The first pediatric lung retransplantation recorded in UNOS took place on September 1, 1989. Since then, re-LTx in children has been associated with lower survival rates compared with primary lung transplantation. However, survival rates after pediatric lung transplantation have improved significantly in the past decade, with the ISHLT reporting five-year survival for pediatric primary transplant recipients of 50% in the most recent era (2002 to June 2007), compared with 43% five-year survival for patients transplanted between 1988 and 1994 [1]. Survival for re-LTx patients has followed suit, with the ISHLT reporting an increase in five-year survival from 32% to 41% over the past two years [1]. Because of these improving results, more patients are presenting for retransplantation, and a growing number of experienced centers have begun to perform pediatric re-LTx. Therefore, an investigation of pediatric lung retransplantation in the United States was undertaken to identify in which patient cohorts it was most effective.

Analysis of the UNOS database demonstrated that graft survival for all re-LTx patients was significantly worse than for primary transplant patients, with a five-year survival of 28% versus 44%. Therefore, it would appear that to generally apply re-LTx to all patients with a failing graft is unjustified, which is not surprising. Also, the subset of lung retransplant recipients that underwent re-LTx less than one year after primary transplant had an even worse survival with a graft half life of 3 months. Therefore, lung retransplantation for this cohort appears unwarranted as well, although clearly even some of these patients survived. For patients who develop bronchiolitis obliterans syndrome, acute rejection, or another condition requiring retransplantation less than one year after their initial transplant, the survival benefit of retransplantation must be carefully weighed against risk, costs, and ethical considerations [8, 9].

However, re-LTx graft survival in certain subsets of patients had similar survival to primary pediatric lung transplantation. Survival for patients who underwent re-LTx more than one year after primary transplant was not significantly different than that of primary transplant recipients. Although survival is not statistically different, the number of patients and events is low, thus increasing the likelihood of a type II error. Therefore, the use of donor organs for this group remains unclear, leaving centers to struggle with these kinds of patients on an individual basis.

By multivariate analysis, ventilator support at the time of re-LTx was shown to be a risk factor for death in this current study. This is a consistent finding in the vast majority of series studying pediatric lung transplantation, and thus it is not surprising that ventilation is associated with mortality post re-LTx [10]. Therefore, those patients who require ventilator support while awaiting their second lung transplant may not be good candidates. Careful consideration of benefit will need to be undertaken for these patients when considering lung retransplantation.

In contrast, graft survival for patients who were retransplanted more than 1 year after their initial transplant and who were not ventilator dependent had the best survival (half life of 4.7 years) of all the re-LTx cohorts investigated and compared favorably with the survival for primary lung transplantation (half life of 4.0 years). Perhaps it is this cohort in whom listing for pediatric lung retransplantation seems most clear for now. Length of time from primary transplant is clearly an important factor, but one that is impacted by the overall health of the patient. While it may be argued that emergent intubation due to acute rejection is fundamentally different than elective intubation that allows a chronically ill patient to be rehabilitated, ventilator dependence nevertheless remains an important factor in survival and one that needs further study.

Lung retransplantation has also been increasing in adults. Before 2005, re-LTx occurred at a rate of less than 40 per year; however, starting in 2005 greater than 70 re-LTx have been performed annually [11, 12]. The re-LTx patients account for roughly 5% of all adult lung transplants, with the number of re-LTx patients aged 50 to 64 growing rapidly over the past decade [12]. The latest ISHLT report documented a nearly twofold increase in 1-year mortality risk for lung retransplant patients [13]. As in children, ventilator support has been demonstrated to be a predictor for poor outcomes in this population, as well as a nonambulatory status [14]. Furthermore, adult re-LTx studies have shown increased mortality in patients undergoing re-LTx less than thirty days after primary transplant, and the best functional results occurring in patients who underwent re-LTx more than 2 years after their initial transplant [11, 15]. While we found that children undergoing re-LTx after an interval of greater than one year had increased graft survival, with increasing numbers of children undergoing re-LTx at greater intervals of time from their initial transplant a further increase in graft survival may be seen. Certainly it appears that elective re-LTx on stable patients who are well removed from their initial transplant yields better outcomes. Further investigation into the most ideal timing for re-LTx will be necessary as this patient population continues to grow.

Renal function is considered an important factor in determining the candidacy of patients for re-LTx, but we were unable to include creatinine clearance in our multivariate analysis because it was only reported in 20% of the study cohort. We did include the need for postoperative dialysis in the univariate analysis, but it was not associated with mortality (p > 0.1). This finding highlights the need to study further what role this important consideration should have when deciding when to list patients for re-LTx.

Pediatric lung retransplantation will no doubt continue to generate controversy, as should any medical procedure of high cost and limited resource. However, a recent small study on pediatric re-LTx patients by Müller and colleagues [16] reports comparable outcomes between primary and re-LTx patients. The current study demonstrates that re-LTx, if performed greater than one year after primary transplantation, and particularly if the patient is not ventilator dependent, no longer seems to have increased morbidity and mortality over primary lung transplantation. When making these difficult decisions to relist a lung recipient, one should consider that patients who have a proven track record of compliance and strong social support networks may maximize a second organ better than many adolescent primary transplant recipients, who are known to often struggle with compliance. This is an important factor when one considers the consensus statement of the ISHLT that assessment of long-term transplantation results should be based primarily on "functional outcome" [17]. Many factors remain relevant to patient selection for re-LTx in addition to the severity of the patient's illness.

Pediatric lung transplantation is a therapy considered by many to have limiting factors, (including the relatively small number of pediatric lung transplant centers and the difficulties of adolescent nonadherence) that cause it to be less widely embraced than adult lung transplantation [18, 19]. However, with the number of lung transplants performed remaining constant, lung retransplantation is a reality that we must face and continue to study so we can apply it in the most efficient manner. Pediatric re-LTx may eventually be seen in similar terms to pediatric heart retransplantation, as a nonideal but inevitable outcome, the safety of which will continue to improve.

Limitations
This study is limited by its retrospective nature, and while the UNOS database contains a large amount of patient data, it cannot replicate patient chart review in its breadth or depth of information (ie, preoperative renal function). Although this 81 patient cohort is the largest series of pediatric re-LTx patients, this number is small and remains limiting for statistical analysis. Also, the authors are confined to the data reported in the database even when the data are not clinically probable, such as 69% of re-LTx patients being on chronic steroids. The authors feel that this is a reporting error as closer to 100% of these patients were probably on steroids. Furthermore, it is always difficult to extrapolate generalizations from group data to individual patients when life and death considerations are involved. Nevertheless, we believe that the conclusions of this study should serve to inform patients, families, physicians, and other caregivers in making difficult decisions. In addition, only patients 18 years of age or less were included in our analysis. While we feel that follow-up into adulthood on these patients would yield valuable results, this was not within the scope of this study.

Conclusion
Since pediatric lung retransplantation began to be performed, it has been reported that retransplanted patients have decreased survival as compared with primary transplant recipients. However, more experienced centers feel that in selective patients it appears to be an effective strategy. We have attempted to identify this selective cohort. For patients less than one year postprimary transplant, in which a significantly worse graft survival can be expected, retransplantation does not appear warranted, as it may be wasting the limited resource of donor lungs. However, for patients greater than one-year post-lung transplant, retransplantation may be a reasonable strategy for endstage graft failure. In particular, those patients greater than one year posttransplant and not ventilator dependent appear to be consistently the most compelling group to retransplant. We believe that pediatric lung retransplantation can be selectively applied to maximize outcomes for patients and the transplant community.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 

  1. Aurora P, Edwards LB, Christie JD, et al. Registry of the International Society for Heart and Lung Transplantation: Twelfth Official Pediatric Lung and Heart/Lung Transplantation Report—2009 J Heart Lung Transplant 2009;28:1023-1030.[Medline]
  2. Huddleston CB, Medeloff EN, Cohen AH, Sweet SC, Balzer DT, Mallory Jr GB. Lung retransplantation in children Ann Thorac Surg 1998;66:199-204.[Abstract/Free Full Text]
  3. Kozower BD, Sweet SC, de la Morena M, et al. Living donor lobar grafts improve pediatric lung retransplantation survival J Thorac Cardiovasc Surg 2006;131:1142-1147.[Abstract/Free Full Text]
  4. Starnes VA, Woo MS, MacLaughlin EF, et al. Comparison of outcomes between living donor and cadaveric lung transplantation in children Ann Thorac Surg 1999;68:2279-2284.[Abstract/Free Full Text]
  5. Kotloff RM. Does lung transplantation confer a survival benefit? Curr Opin Organ Transplant 14:499–503.
  6. Liou TG, Adler FR, Cox DR, Cahill BC. Lung transplantation and survival in children with cystic fibrosis N Engl J Med 2007;357:2143-2152.[Medline]
  7. Sweet SC. Update on pediatric lung allocation in the United States Pediatr Transplantation 2009;13:808-813.
  8. Novick RJ, Schäfers HJ, Stitt L, et al. Seventy-two pulmonary retransplantations for obliterative bronchiolitis: predictors of survival Ann Thorac Surg 1995;60:111-116.[Abstract/Free Full Text]
  9. Novick RJ, Schäfers HJ, Stitt L, et al. Recurrence of obliterative bronchiolitis and determinants of outcome in 139 pulmonary retransplant recipients J Thorac Cardiovasc Surg 1995;110:1402-1414.[Abstract/Free Full Text]
  10. Stillwell PC, Mallory Jr GB. Pediatric lung transplantation Clin Chest Med 1997;18:405-414.[Medline]
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  12. Magee JC, Barr ML, Basadonna GP, et al. Repeat organ transplantation in the United States, 1996–2005 Am J Transplant 2007;7(5 Part 2):1424-1433.[Medline]
  13. Christie JD, Edwards LB, Aurora P, et al. The Registry of the International Society for Heart and Lung Transplantation: Twenty-sixth official adult lung and heart-lung transplantation report-2009 J Heart Lung Transplant 2009;28:1031-1049.[Medline]
  14. Strueber M, Fischer S, Gottlieb J, et al. Long-term outcome after pulmonary retransplantation J Thorac Cardiovasc Surg 2006;132:407-412.[Abstract/Free Full Text]
  15. Novick RJ, Stitt LW, Al-Kattan K, et al. Pulmonary retransplantation: predictors of graft function and survival in 230 patients. Pulmonary Retransplant Registry. Ann Thorac Surg 1998;65:227-234.[Abstract/Free Full Text]
  16. Müller C, Görler H, Ballmann M, et al. Pulmonary retransplantation in paediatric patients: a justified therapeutic option? A single-centre experience Eur J Cardiothorac Surg 2010[epub ahead of print].
  17. Reichenspurner H, Girgis RE, Robbins RC, et al. Stanford experience with obliterative bronchiolitis after lung and heart-lung transplantation Ann Thorac Surg 1996;62:1467-1473.[Abstract/Free Full Text]
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